DIURNAL-VARIATION IN KAINATE-INDUCED AP-1 ACTIVATION IN RAT-BRAIN - INFLUENCE OF GLUCOCORTICOIDS

The large diurnal rhythm of circulating glucocorticoid levels was used to determine if physiological fluctuations of glucocorticoids were ca pable of modulating kainate-induced immediate early gene (IEG) activat ion, measured as AP-1 DNA binding activity, in rat brain since adminis tered dexamethasone previously had been shown to be inhibitory. AP-1 a ctivity in the cerebral cortex 1.5 h after kainate treatment measured at 08.00 h (4.9-fold control) was more than twice the stimulation obta ined at 16.00 h (1.8-fold). These times of day are associated with rep orted low and high levels of circulating glucocorticoids at 08.00 and 16.00 h, respectively. To test if there was a causal relationship, kai nate-induced AP-1 activity was measured at both times in adrenalectomi zed rats. Adrenalectomy abolished the attenuation of the response to k ainate found in intact rats at 16.00 h, indicating that the diurnal fl uctuations in circulating glucocorticoids contribute to modulation of IEG responses to kainate. Neither AP-1 activity in the hippocampus nor cyclic AMP response element activation in either brain region measure d after kainate treatment was influenced by the time of day or by adre nalectomy. Immunoprecipitation of glucocorticoid receptors from cortic al nuclear extracts co-precipitated c-Jun, indicating that the mechani sm accounting for the supppression of AP-1 activity by glucocorticoids may involve direct interactions between activated glucocorticoid rece ptors and AP-1 constituent proteins. These results extend previous rep orts that administered glucocorticoids inhibit AP-1 activity by demons trating that this occurs with endogenous glucocorticoids as a conseque nce of the circadian rhythm of circulating glucocorticoids and demonst rate that responses to kainate vary dependent upon the time of day.